APPLICANT'S ABSTRACT: Marijuana is one of the oldest drugs of abuse. Although its active ingredients have a long history of use as therapeutic agents for a variety of maladies, its psychoactive actions limit its current use in Western medicine. There is also evidence that immunosuppression results from chronic marijuana use. The central cannabinoid receptor from brain, and more recently, the peripheral cannabinoid receptor from a promyelocytic leukemic cell line, have been cloned. In Phase I of this project, stable cell lines expressing either the brain or the peripheral receptor subtype will be established and will be used to develop a high throughput screening program to screen for potent and selective agonists and antagonists. Macrophage cell lines and cell lines expressing either receptor subtype will also be used to study the signaling pathways employed by the two receptors. The goal is to identify new therapeutic agents that would have the desirable immunosuppressive and anti- inflammatory effects mediated by the peripheral cannabinoid receptor, but devoid of central psychoactive effects.